Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Area of Science:

• Neuro-oncology
• Genomics
• Molecular Pathology

Background:

• Lower-grade gliomas (WHO grades II and III) exhibit variable clinical behavior not fully predicted by histology.
• Interobserver variability in histologic diagnosis complicates accurate grading and prognostication.
• Mutations in IDH, TP53, and 1p/19q codeletion are recognized as clinically relevant markers.

Purpose of the Study:

• To integrate genomewide data from multiple platforms to classify lower-grade gliomas.
• To identify molecular subtypes that correlate with clinical outcomes.
• To compare the accuracy of molecular classification with traditional histologic grading.

Main Methods:

• Genomewide analyses of 293 lower-grade gliomas using exome sequencing, copy number, methylation, and gene/microRNA expression data.
• Integration of multi-platform data for unsupervised clustering and correlation with clinical outcomes.
• Analysis of mutations in IDH, TP53, ATRX, and 1p/19q codeletion status.

Main Results:

• Three robust, nonoverlapping, prognostically significant molecular subtypes of lower-grade glioma were identified.
• Molecular classification based on IDH, 1p/19q, and TP53 status was more accurate than histologic class.
• Gliomas with IDH mutation and 1p/19q codeletion showed the most favorable outcomes; those without IDH mutation resembled glioblastoma.

Conclusions:

• Genomewide data integration delineated three molecular classes of lower-grade gliomas, surpassing histologic classification in accuracy.
• Lower-grade gliomas with IDH mutation are characterized by either 1p/19q codeletion or TP53 mutation.
• Most lower-grade gliomas lacking IDH mutation share molecular and clinical similarities with glioblastoma.